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An alternative approach to protecting the heart under ischaemic stress

C.X. Qin, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia.

Formyl peptide receptors (FPR) are integral to inflammation regulation and are thus attractive therapeutic targets for myocardial ischaemia-reperfusion (I-R) injury. Dual FPR1/FPR2 agonists potentially offer FPR1-mediated cardiomyocyte preservation together with FPR2 inflammation-limiting actions. We investigated the cardioprotective potential of two small-molecule FPR agonists on myocardial I-R injury in vivo and their FPR1/FPR2 signalling fingerprints in vitro. Mice subjected to coronary artery occlusion were administered the pyridazin-3-(2H)-one compound-17b (Cmpd17b), Amgen compound-43 (Cmpd43) or vehicle commencing just prior to reperfusion. Significant cardioprotective effects of Cmpd17b (but not Cmpd43) were evident on cardiac necrosis (infarct size and cardiac troponin I after 24h), circulating leukocytes and neutrophil infiltration (after 48h) and adverse cardiac remodelling (after 7-days reperfusion); Cmpd17b similarly exhibited superior cardioprotection in isolated cardiomyocytes and cardiac fibroblasts in vitro. Both agonists elicited concentration-dependent activation of multiple intracellular signaling pathways, including Ca2+ mobilization and phosphorylation of ERK1/2, Akt1/2/3(Thr308) and Akt1/2/3(Ser474). Statistical evaluation of the signal transduction established that, relative to Cmpd43, Cmpd17b exhibited a significant 30-fold bias away from intracellular Ca2+ mobilization. These findings reveal ligand-selective cardioprotection with the dual FPR1/FPR2 agonist Cmpd17b both in vitro and in vivo, with significant limitation of cardiac necrosis, inflammation and remodelling up to 7-days post-I-R. The biased signalling profile of Cmpd17b is a possible contributing mechanism to its superior cardioprotection, providing a new approach for development of small-molecule FPR pharmacotherapies for myocardial infarction.